The present invention relates to a sleep-inducing pharmaceutical composition and a method of inducing sleep that is highly effective, but causes few, if any, side-effects. There has long been a need for such a sedative, because the sedatives presently available either are not effective enough or cause significant side-effects.
It is known that the amino acid L-tryptophan possesses sedative qualities (Oates and Sjoerdsma, Neurology 10: 1076-1078, 1960), and in 1970 (Wyatt et al, Lancet 842-46) it was suggested that L-tryptophan might be used as a natural sedative. Other amino acids may also affect sleep: cystathionine induces a sleeplike EEG in cats (Key and White, Neuropharmacology 9: 349-57, 1970); L-lysine (Chang et al, Life Sciences 28: 407-13, 1981) and amino acid mixtures given intravenously to humans enhance non-REM sleep (Lacey et al, Electroenceph. Clin. Neurophysiol. 44: 275-80, 1978).
L-tryptophan has not, however, been widely used as a sedative, probably because of the large quantity (bulk) of L-tryptophan that is needed to induce sleep. Thus, the smallest quantity that has been found to successfully initate sleep is one gram. Hartman and Spinweber (J. of Nervous and Mental Disease, 167: 4, 497-99, 1979) found that one gram of L-trytophan decreased sleep latency in normal men by about 50 percent. One-half gram had no effect.
One way to reduce the quantity (bulk) of L-tryptophan needed to induce sleep would be to combine it with another active substance. Such an approach is suggested by Koella (U.S. Pat. No. 4,161,530), who discloses combining L-tryptophan with beta-receptor-blocking compounds. The principal disadvantage of this approach is that there is no evidence that the effects are more than additive and that the addition of the beta-receptor-blocking compounds does not detract from the endogenous qualities of tryptophan. The beta-receptor-blockers are not naturally present in humans and are likely to have unknown, but significant side-effects.
It has been known, however, that there are other naturally occurring substances that produce sedation. The cations, magnesium and calcium, when injected directly into the brains of animals produce sedation. Kleitman, Sleep and Wakefulness 200-02 (1939). Erickson et al (Science 199: 1219-21, 1978) have found that when the cations magnesium, calcium, or cadmium are injected directly into the brains of mice they potentiate the sedative effects of ethanol. Similarly, peripheral injections of manganese (Harris, Pharmacol. Biochem. Behav. 10: 527-34, 1979) and beryllium (Ribeiro, Proc. West. Pharmac. Soc. 13:13, 1970) potentiate ethanol-induced sedation, and rubidium may enhance diazepam-induced sleeping time (Mannisto and Saarnivaara, Brit. J. Anaes. 48: 185-89, 1976). Calcium when given orally by itself is known to have mild sedative properties in humans (Carman and Wyatt, Biological Psych. 14: 295-336, 1979).